International Patent Publication No. WO 92/22554 describes a series of sigma receptor ligands considered useful for the treatment of a range of psychic and neurological disorders. The structure activity relationship of these compounds has been further investigated by Perregaard, J. et al., J. Med. Chem., 1995, 38, 11,p. 1998-2008.
Among other compounds, International Patent Publication No. WO 92/22554 discloses the compound 1'-[4-[1-(4-fluorophenyl)-1H-indole-3-yl]-1-butyl]-spiro[isobenzofuran-1(3 H),4'-piperidine], ##STR1##
which is the subject of the present invention. This compound was shown in Perregaard, J. et al., J. Med. Chem., 1995, 38, 11, p. 1998-2008 to be a potent and selective sigma ligand, in particular a sigma, ligand. Furthermore, the anxiolytic potential of the compound was tested in the black/white exploration test in rats, which is an animal model predictive for effect in the treatment of generalised anxiety disorder. It was found to be active over a large dose range. Results of further tests in generalised anxiety disorder models are reported in J. Pharmacol Exp Ther., 1997, 283, No. 2.
Co-pending Danish patent application No. 0071/98 discloses the effect of the compound in the treatment of addiction to drugs and other substances of abuse.
Evidence has been presented from studies of the biology and function of sigma receptors that sigma receptor ligands may be useful in the treatment of a range of psychic and neurological disorders, including psychosis and movement disorders, such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J. M. et al. Pharmacological Reviews, 1990, 42, 355). The known sigma receptor ligand, rimcazole, clinically shows effects in the treatment of psychosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry, 1989, 1, 7) and a group of sigma receptor ligands have been described to show antihallucinogenic activity in animal models (International Patent Publication No. WO 9103243).
Sigma receptor ligands have also been reported to be involved in modulation of NMDA receptor mediated events in the brain and to act as anti-ischemic agents in in vivo tests (Rao, T. S. et al,. Molecular Pharmacology, 1990, 37, 978). In addition to ischemia, the sigma receptor ligands may also be useful in the treatment of other such NMDA receptor mediated events, e.g. epilepsy and convulsion.
Also, some sigma receptor ligands have been found to show anti-amnesic effects in an animal model (Early et al., Brain Research, 1991, 546, 281-286). Sigma ligands have been shown to influence central acetylcholine levels in animal models (Matsuno et al, Brain Research, 1992, 575, 315-319; Junien et al, Eur. J. Pharm., 1991, 200, 343-345) and may, therefore, have potential in the treatment of senile dementia of the Alzheimer type.
Finally, some guanidine derivatives having sigma receptor activity have been disclosed to be useful as anxiolytics (International Patent Publication No. WO 9014067) and some sigma receptor ligands have been found to bind to the cocaine binding site on the dopamine transporter and others have been found to inhibit dopamine uptake (Izenwasser, S., et al, Eur. J. Pharmacol., 243, 201-205 and Woodward, J. J. and Harms, J., Eur. J. Pharmacol., 210, 265-270.
Diseases associated with panic attacks as a major element include panic disorder, specific phobias and agoraphobia. Specific phobias and agoraphobia both occur with or without panic attacks. According to DSM IV panic disorder, specific phobias and agoraphobia constitute distinct sub-classes of psychic illnesses and it is widely recognised that it is possible to differentiate these disorders from generalised anxiety disorder with respect to diagnostic, genetic (Kendler K. S. et al., Arch Gen. Psychiatry., 1995, 52, 347-383) and pharmacological criteria.
Generalised anxiety disorder is treated with benzodiazepines such as diazepam and midazolam which are not employed in the treatment of panic and 5HT.sub.1A receptor agonists such as buspirone which is reported to be ineffective in the treatment of panic (Fulton B. and Brogden R. N. Buspirone: CNS Drugs, 1997, 7(1), 68-88). The therapies of choice in panic and in other panic associated disorder include high potency benzodiazepines and compounds normally associated with the treatment of depression. Selective serotonin re-uptake inhibitors produce a significant reduction in the severity of the symptoms associated with panic and are better tolerated than the alternative treatments (Bertani A. et al., Depression and Anxiety, 1997, 4, 253; Sheehan and Harnett-Sheenan, J.Clin.Psychiatry, 1996, 57(suppl. 10), 51-60). As a result they are now becoming first choice treatments in panic disorder. The serotonin re-uptake inhibitors are not useful in the treatment of generalised anxiety disorder.
Studies have shown that patients suffering from panic attacks, in particular in association with agoraphobia, have a quality of life impairment comparable with or greater than the disability found in patients with alcoholism, schizophrenia or personality disorders. Furthermore the current treatments are not always effective or cause unacceptable side-effects.
Consequently, there is a need for alternative therapies useful in the treatment of disorders associated with panic attacks.
It has now, surprisingly, been found that the compound of the invention shows a beneficial effect in the treatment of panic attacks.